Generalized resistance to thyroid hormone (GRTH) is an inherited disease linked to mutations in the beta T3 receptor gene and characterized clinically by the resistance of peripheral and pituitary tissues to the action of thyroid hormone. Of the over 30 different mutations identified in the ligand binding domain of the beta receptor, several were shown to inhibit normal receptor function by a dominant negative mechanism which is likely to mediate the phenotype of this disease. Recent studies have indicated that this dominant negative effect is most likely mediated by competition of mutant and normal receptor for binding to T3 response elements within various thyroid hormone responsive genes. We have also recently investigated whether the heterogeneous phenotypic features that occur within and among kindreds might be due to differential expression of mutant vs. normal receptors in various tissues. Using an allele-specific primer extension method, we have determined that in certain patients there is a great excess of expression of the mutant messenger RNA which may correlate with more severe tissue resistance. The mechanism for such differential expression is currently being examined. We have also investigated the relationship between GRTH and attention deficit hyperactivity disorder. We studied a large population of well characterized patients consisting of 49 affected and 55 unaffected family members comprising a total of 52 adults and 52 children. Attention deficit hyperactivity disorder was found in 70% of affected children compared to 20% of unaffected family members. In addition, thyroid hormone therapy appeared to ameliorate the hyperactivity symptoms in certain patients. Certain of the patients with the hyperactivity disorder were also studied by positron emission tomography. Of the 60 regions measured by positron emission tomography, glucose metabolic rates were significantly decreased in the superior right parietal lobes and increased in the mid-occipital lobes, suggesting that such changes in glucose metabolism may be related to abnormalities of sustained attention. These data demonstrate that an attention deficit hyperactivity disorder is strongly and specifically associated with generalized resistance to thyroid hormone. This is the first defined molecular model of hyperactivity and may provide new insights into the basic pathogenesis of this disorder.